A second-generation total synthesis of spirastrellolide A methyl ester

Article abstract of DOI:10.1002/anie.201108594

Marine macrolides: An improved second-generation total synthesis of the anticancer macrolide spirastrellolide A methyl ester has been achieved. The synthesis features a uniformly high level of stereocontrol combined with more expedient fragment assembly, and demonstrates a critical dependence of the crucial macrolactonization step on the substitution pattern of the C22-C24 linker region. Copyright

Full text of DOI:10.1002/anie.201108594

Angewandte
Chemie
DOI: 10.1002/anie.201108594
Natural Product Synthesis
A Second-Generation Total Synthesis of Spirastrellolide A Methyl
Ester**
Ian Paterson,* Philip Maltas, Stephen M. Dalby, Jong Ho Lim, and Edward A. Anderson
Dedicated to Professor Gilbert Stork on the occasion of his 90th birthday
Marine macrolides that selectively disrupt cell cycle events
represent important lead compounds for anticancer drug
discovery,[1,2] as highlighted by the recent development of
Halaven (a fully synthetic analogue of the halichondrins) for
the treatment of metastatic breast cancer.[3] Notable amongst
this group are the spirastrellolides, a family of complex
macrocyclic polyketides isolated from the Caribbean sponge
Spirastrella coccinea, of which the first to be reported (in
2003) and most abundant member is spirastrellolide A (1,
Scheme 1).[4] However, structural and stereochemical deter-
mination was not completed until 2007, following the
identification and derivatization of six closely related con-
geners, spirastrellolides B–G.[5] Isolated as their methyl ester
derivatives (e.g. 2), these architecturally complex 38-mem-
bered macrolides exhibit uniformly strong activity and an
unusual phenotypic response in a cell-based antimitotic assay,
which has been shown to be mediated through potent and
selective inhibition of protein phosphatase 2A (IC50 = 1 nm
for 1). As drugs that target the inhibition of protein
phosphatases have already shown considerable therapeutic
value in fields tackling cancer and other metabolic disor-
ders,[6] the synthesis and evaluation of novel PP2A inhibitors
based on the spirastrellolide scaffold is of significant current
interest.
Testament to the acute challenge presented by these
spiroacetal macrolides, and despite intense research
efforts,[7–9] only three completed syntheses of the spirastrello-
lides have been reported to date: the first total synthesis of
spirastrellolide A methyl ester 2 by our group,[10] and two
subsequent syntheses of the 15,16-dihydro congener, spira-
strellolide F methyl ester, by the Fꢀrstner group.[11,12] Evolv-
ing alongside the structure determination studies undertaken
by the Andersen group, our first-generation total synthesis of
2 tackled the double challenge of constructing the fragments
whilst maintaining the flexibility required to access any of the
[*] Prof. I. Paterson, Dr. P. Maltas, Dr. S. M. Dalby, Dr. J. H. Lim,
Dr. E. A. Anderson
University Chemical Laboratory
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: ip100@cam.ac.uk
Homepage: http://www-paterson.ch.cam.ac.uk/
[**] This work was supported by the EPSRC, Clare College, Cambridge
Scheme 1. 2nd generation retrosynthetic analysis of spirastrellolide A
methyl ester. Bn=benzyl, PMB=para-methoxybenzyl, TBS=tert-butyl-
dimethylsilyl, TES=triethylsilyl.
(S.M.D.), Homerton College, Cambridge (E.A.A.), and SK Innova-
tion (J.H.L.). We thank Dr. Julien Genovino (Cambridge) for valuable
experimental contributions, and the EPSRC national mass spec-
trometry service (Swansea) for mass spectra.
possible spirastrellolide diastereomers. Following this syn-
thesis and freed of such restrictions, we now report a signifi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108594.
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cantly improved second-generation total synthesis of 2 that
features uniformly high levels of stereocontrol combined with
more expedient fragment assembly, in which the crucial
macrolactonization step is found to exhibit a critical depend-
ence on a free C23 alcohol in the fully elaborated C1–C47
seco acid.
A key modification to this second-generation synthesis
was simplification of side-chain attachment through prepara-
tion of the complete C1–C47 carbon backbone (3) prior to
macrolactonization (Scheme 1).[13] The corresponding C1–
C47 seco acid 3 would be accessed using a cross-coupling
reaction between C43–C47 stannane 4 and C1–C42 cyclic
carbonate 5. This revised approach would allow for stereo-
controlled installation of the required E,Z skipped diene
while simultaneously freeing the C37 hydroxy group for
macrolactonization, thereby reducing reliance on protecting
groups.
Cyclic carbonate 5 would be generated from a g-lactone
fused to the F ring. Building on our earlier studies, the BC-
spiroacetal would be installed through PMB deprotection/
in situ spiroacetalization of a Z enone arising from coupling
of the C1–C16 alkyne fragment 6 and C17–C40 aldehyde 7.
Bond scission at C24/C25 then reveals two intermediates we
had employed previously: the C17–C24 vinyl iodide 8[10a] and
the C26–C40 DEF-bis(spiroacetal) 9.[8d]
As shown in Scheme 2, synthesis of C17–C40 aldehyde 7
commenced with selective desilylation of DEF-bis(spiroace-
tal) 9 to afford the corresponding C26 alcohol, which was then
oxidized (DMP, NaHCO3) and methylenated (H3CPPh3Br,
nBuLi) to give the C25–C40 alkene 10 in 70% overall yield.
Hydroboration of alkene 10 with 9-BBN provided the
corresponding trialkylborane which was then subjected to
a highly effective B-alkyl Suzuki coupling[14] with vinyl iodide
8, mediated by [PdCl2(dppf)], which delivered diene 11 in
essentially quantitative yield.
Scheme 2. Preparation of C17–C40 aldehyde 7. a) PPTS, CH2Cl2/MeOH
(12:1), 08C, 88%; b) DMP, NaHCO3, CH2Cl2; c) Ph3PCH3Br, nBuLi,
THF, À788C to RT, 80% (over 2 steps); d) 9-BBN, THF; H2O; 8,
[PdCl2(dppf)], Ph3As, Cs2CO3, THF/DMF (1:1), >95%; e) BH3·SMe2,
THF; MeOH, 30% H2O2, 1m NaOH, 08C to RT; f) TESOTf, 2,6-
lutidine, CH2Cl2, À788C, 85% (over 2 steps, d.r. 10:1); g) TBAF,
AcOH, THF, >95%; h) H2, Raney-Ni, EtOH, 97%; i) TEMPO, BAIB,
CH2Cl2/pH 7 buffer (5:1), >95%. 9-BBN=9-borabicyclo[3.3.1]nonane,
BAIB=[bis(acetoxy)iodo]benzene, DMF=N,N-dimethylformamide,
DMP=Dess–Martin periodinane, dppf=1,1’-bis(diphenylphosphanyl)-
ferrocene, PPTS=pyridinium para-toluenesulfonate, TBAF=tetrabuty-
lammonium fluoride, TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy free
radical.
Installation of the requisite hydroxy groups at C17 and
C23, with the necessary configuration at C23/C24, was then
carried out through a substrate-controlled double hydro-
boration of diene 11. Significant enhancement in the diaste-
reoselectivity of this key transformation was realized by
exploiting a marked substrate concentration dependence.
Under optimized conditions, diene 11 was added dropwise
.
over 2 h via syringe pump to a solution of BH3 SMe2 in THFat
08C. Oxidative workup (H2O2, NaOH) and persilylation of
the crude triol then provided the tetra-TES ether 1 in
excellent yield and diastereoselectivity (85%, 10:1 d.r.).
Selective deprotection to remove the more labile C17 and
C37 TES ethers, followed by debenzylation, gave triol 13 in
> 95% yield. At this stage, completion of the targeted C17–
C40 fragment 7 was conveniently and efficiently accom-
plished through a one-pot, triple oxidation at C17 and C40
(TEMPO/PhI(OAc)2) which proceeded with concomitant
lactonization.[15]
With the modified C17–C40 aldehyde 7 in hand, coupling
with the C1–C16 framework was required (Scheme 3). Initial
attempts involving exposure of the lithium acetylide of 6 to
aldehyde 7 led predominantly to decomposition, which is
thought to relate to complications arising from the g-lactone
moiety.[16] After a degree of experimentation, smooth cou-
pling of the corresponding iodoalkyne 14 with aldehyde 7 was
accomplished under Nozaki–Hiyama–Kishi conditions
(NiCl2, CrCl2).[17] The resulting C1–C40 propargylic alcohols
15 were subjected to Lindlar reduction (H2, Pd/CaCO3/Pb,
quinoline) and Dess–Martin oxidation to provide the corre-
sponding Z enone in 72% yield over the two steps. Bis-PMB
deprotection (DDQ, 0 8C) and in situ spiroacetalization then
provided C1–C40 BC-spiroacetal 16 as a single diastereomer
(82%), without accompanying deprotection of the C23 TES
ether as observed previously—a seemingly minor detail which
later proved to be of great consequence.[10b]
With C1–C40 heptacycle 16 in hand, our attention turned
to the installation of the side chain to complete the C1–C47
carbon backbone of spirastrellolide A (Scheme 4). Accord-
ingly, selective C1 desilylation followed by partial reduction
of the g-lactone (DIBALH) and addition of vinylmagnesium
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Scheme 3. Completion of the C1–C40 spirastrellolide A heptacycle 16.
a) NIS, AgNO3, THF, 94%; b) CrCl2, NiCl2, THF, 85%; c) Pd/CaCO3/
Pb, quinoline, H2, EtOAc; d) DMP, NaHCO3, CH2Cl2, 72% (over 2
steps); e) DDQ, CH2Cl2/pH 7 buffer (9:1), 08C, 82%. DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone, DMAP=4-(dimethylamino)pyr-
idine, NIS=N-iodosuccinimide.
bromide provided allylic alcohol 17 (80% over 3 steps), as an
inconsequential 3:2 epimeric mixture of C40 alcohols. Treat-
ment of triol 17 with triphosgene to selectively generate the
C37–C40 cyclic carbonate, followed by oxidation of the
remaining alcohol at C1, afforded the C1–C42 carboxylic acid
5, ready for the planned p-allyl Stille cross-coupling reac-
tion.[18] Following optimization in model studies,[10b] we were
pleased to observe the smooth coupling of 5 with the C43–C47
stannane 4 using catalytic [PdCl2(MeCN)2] in wet DMF,
which afforded C1–C47 diene 3 as a single E,Z isomer in 86%
yield. Notably, this protocol for assembling the full spirastrel-
lolide side chain on a linear intermediate was found to be
significantly more efficient than our earlier route using olefin
cross-metathesis in the presence of the sterically demanding
macrolactone core.
Scheme 4. Preparation of spirastrellolide A seco acid 3. a) HF·py, py,
THF, 89%; b) DIBALH, CH2Cl2, À788C, >95%; c) vinyl-MgBr, THF,
08C to RT, 91%; d) triphosgene, py, Et3N, CH2Cl2, À788C, 82%;
e) TEMPO, BAIB, CH2Cl2/pH 7 buffer (5:1); f) NaClO2, NaH2PO4,
tBuOH/H2O/THF (1:1:1), 80% (2 steps); g) [PdCl2(MeCN)2], 4, DMF/
H2O/THF (8:2:1), 86%; h) K2CO3, MeOH, 95%. DIBALH=diisobuty-
laluminium hydride, py=pyridine.
a truncated side chain, to undergo productive macrolactoni-
zation suggested this could not be solely a consequence of
structural variation in this region.[20] This frustrating outcome
is particularly surprising given the structural homology of 18
to the previously successful substrate 19, and suggested to us
that these macrolactonization failures possibly arose from
a subtle conformational influence from the C23 TES ether,
serendipitously a free alcohol for 19, preventing closure of the
38-membered macrocycle.
To test the hypothesis of a protecting group dependence at
the C23 position located in the linker domain between the BC
and DEF spiroacetal ring systems, C1–C47 carboxylic acid 3
was subjected to mildly acidic conditions (PPTS, CH2Cl2/
MeOH). Depending on the duration of the reaction, this gave
access to either diol 20 (mono-desilylation to form the C23
alcohol) or triol 21 (bis-desilylation to form the C22/C23 diol).
In our earlier synthesis, Yamaguchi macrolactonization[19a]
of the corresponding C1–C40 hydroxy acid 19 (Scheme 5) had
proceeded in excellent yield (> 95%), which we presumed
reflected a highly favorable conformational pre-organization
of the (side-chain truncated) seco acid.[10b] Macrolactoniza-
tion of 3 was therefore expected to proceed with similar
facility, yet no macrocyclic products were isolated when 3 was
submitted to a wide range of macrolactonization conditions
(including Yamaguchi, Keck and Shiina),[19] with only degra-
dation of the starting material observed. Similarly, the failure
of the C1–C42 diol 18 (shown in Scheme 4), which contains
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In conclusion, we have achieved a much-improved total
synthesis of the antimitotic marine macrolide spirastrellolide
A methyl ester (2) that proceeds in 6% yield over 23 steps
from the key DEF-bis(spiroacetal) intermediate 9.[21] This
second-generation route features a uniformly high level of
stereocontrol combined with rapid fragment assembly, and
should be readily amenable to the synthesis of useful
quantities of this scarce anticancer agent, along with other
congeners and analogues, for further biological studies.
Surprisingly, a free C23 alcohol in the fully elaborated C1–
C47 seco acid (3) was found to be essential for the realization
of a smooth and high-yielding macrolactonization, where this
hydroxy group presumably contributes to a favorable con-
formational pre-organization of the southern hemisphere—
a finding which exemplifies the unanticipated challenges that
are often faced in tackling the chemical synthesis of complex
natural products.
Received: December 6, 2011
Published online: February 6, 2012
Keywords: anticancer agents · marine macrolides ·
.
natural products · spiroacetals · total synthesis
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[20] We attribute this remarkable result to favorable conformational
pre-organization of the C22–C24 linker region for alcohols 20
and 21, not adopted by bis-TES ether 3, which serves to direct
the BC- and DEF-spiroacetals in a productive manner for
closure of the 38-membered macrolactone. This effect may
derive from possible hydrogen bonding of the free C23 alcohol
with the C11 ether, according to that observed in the crystal
structure of
a macrocyclic pentaol obtained previously
(Ref. [10b]). Alternatively, alleviating the steric hindrance
imposed by the vicinal TES ethers may permit stereoelectronic
control of the C22/C23 conformation to predominate. The
forcing conditions required by Fꢀrstner (refluxing PhMe) for
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acetal; see Ref. [11b].
[21] In comparison, our first-generation synthesis (Ref. [10b]) pro-
ceeded in ca. 1% yield over 25 steps from 9.
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